Immunoconjugates are promising candidates for the treatment of different medical indications, in particular for the treatment of a wide variety of cancers. For example, Tassone et al. (2004) reports excellent cytotoxic activity of the maytansinoid immunoconjugate B-B4-DM1 against CD138 positive multiple myeloma cells (see also US Patent Publ. 20070183971).
The publications and other materials, including patents, used herein to illustrate the invention and, in particular, to provide additional details respecting the practice are incorporated by reference. For convenience, the publications are referenced in the following text by author and date and are listed alphabetically by author in the appended bibliography.
A substantial body of research has concentrated on the development of systems in which an effector agent can be selectively delivered to a desired location or cell population, i.e., systems for a more targeted treatment of ailments with fewer toxic side effects. In spite of considerable progress that has been made, many of those delivery systems for the treatment of various diseases, for example, the treatment of cancer, are still ineffective and/or subject the patient to considerable risk.
Immunoconjugates comprise at least one targeting agent attached to at least one effector molecule. Such immunoconjugates can be categorized according to their effector molecules into, for example, drug immunoconjugates, immunotoxin conjugate and radioimmunoconjugates (Payne, 2003).
Efficiency in killing target cells is one key factor in the usefulness of an immunoconjugate. Efficiency can be influenced by the potency of the effector molecule (Blättler and Chari, 2001), by the ability of the effector to retain its potency (Chari et al., 1995; Liu et al., 1996; Ojima et al., 2002; Senter et al., 2002 and Sievers and Linenberger, 2001), by the tumor accessibility (Charter, 2001), by the level of expression of the target antigen on the target cell, by targeting agent affinity, and by the ability of the target cell to internalize the immunoconjugate (Wargalla, 1989).
One approach towards better efficiency involves the radioimmunoconjugate Zevalin. Y-90 Zevalin (Yttrium-90-labeled Ibritumomab-Tiuxetan) and In-111 Zevalin (Indium-111-labeled Ibritumomab-Tiuxetan) are radioimmunconjugates (Biogen-IDEC) based on Ibritumomab, the murine counterpart of Rituximab, conjugated with the chelator Tiuxetan, that has affinity for In-111 and Y-90. Both Ibritumomab (murine) and Rituximab (human), bind to CD20 which is widely expressed on B cells. CD20 does not internalize, modulate or shed and most likely plays a role in the Ca2+ in- and efflux of cells. Rituximab when administered by itself (without Zevalin) is highly cytotoxic and results in the elimination of B cells (including cancerous B cells) and thus has become part of the standard treatment of aggressive lymphomas. The eliminated B cells are replaced by healthy B cells from lymphoid stem cells.
The Zevalin therapeutic regime involves both the unconjugated antibody Rituximab and the immunoconjugate Zevalin. Generally, a single infusion of Rituximab precedes a fixed dose of In-111 Zevalin administered as a 10 minutes IV push. This step is, after seven to nine days, followed by a second step that involves a second infusion of Rituximab prior to administration of Y-90 Zevalin as a 10 minutes IV push. The pre-treatment with Rituximab removes the bulk of B cells, while the remaining cells, which may include tumor cells resistant to treatment with Rituximab, can then be targeted with Zevalin. In-111/Y-90 Zevalin is generally not employed by itself due to side effects that would result from the B cell mediated distribution of the radioactivity throughout the patient's body.
This Zevalin treatment, which is indicated for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma, including patients with Rituximab refractory follicular non-Hodgkin's lymphoma, showed higher response rates in clinical trials compared to only Rituximab. It also showed promising results for patients who no longer responded to Rituximab.
Ideally an immunoconjugate specifically binds to the target cell population, such as a particular class of tumor cells, and hardly or not at all to any other cell, in particular not to cells that perform vital functions in the host organism. While some antigens well correlate to certain disease profiles, in the majority of cases the antigens are also expressed on cells that are not associated with the disease, that is, non-target cells. Depending on the importance of these healthy cells for the organism, the success of an immunoconjugate will to a large extent depend on how far these cells are affected by the treatment.
Thus, there remains a need for reducing the potential of side effects of immunoconjugates resulting from their interaction with non-targets that express the relevant antigen of the target cells. These include, in particular, cytotoxicity towards non-target cells as well as the overall reduction in efficiency of the immunoconjugate due to association with target molecules that have dissociated from the target cells. The reduction of cytotoxicity towards non-target cells is particularly important when the non-target cells play a vital role in the host system.